This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We propose to investigate the arrhythmogenic consequences of regional acidosis within the cardiac ultrastructure by developing a hierarchical series of novel integrative 3D models which will incorporate increasingly more complex details of the subcellular architecture, spatial heterogeneities of protein distribution, and interacting effects of protons on normal Ca2+ and Na+ transport and ECC. These models will be used to predict 1) pH gradients resulting from heterogeneity of acid-base transporters around a single t-tubule, 2) potential interactions of pH gradients on normal Ca2+ and Na+ transport around a single t-tubule and 3) consequences of the pH gradients on normal ECC in an anatomically accurate cross-section of a ventricular cell.